Angiotensin II and Potassium Regulate Aldosterone Production: the Expression of Steroidogenic Enzymes and Type 1 Angiotensin II Receptors in a Newly Developed Adrenocortical Cell Line

Introduction: Transgenic rats expressing the human (pro)renin receptor (h(P)RR) have elevated plasma aldosterone levels despite unaltered levels, in plasma and adrenal, of renin and angiotensin II. Materials and methods: To investigate whether renin/prorenin–(P)RR interaction underlies these elevated aldosterone levels, the effect of (pro)renin on steroidogenesis was compared with that of angiotensin II in two (P)RR-expressing human adrenocortical cell lines, H295R and HAC15. Angiotensin II rapidly induced extracellular signal-regulated kinase (ERK) phosphorylation and increased the expression of STAR, CYP21A2, CYP11B2, and CYP17A1 at 6 and 24 hours, whereas the expression of CYP11A1 and HSD3B2 remained unaltered. Incubation with renin or prorenin at nanomolar concentrations had no effect on the expression of any of the steroidogenic enzymes tested, nor resulted in ERK phosphorylation. Angiotensin II, but not renin or prorenin, induced aldosterone production. Conclusion: Although the (P)RR is present in adrenocortical cells, renin and prorenin do not elicit ERK phosphorylation nor directly affect steroid production via this receptor at nanomolar concentrations. Thus, direct (pro)renin–(P)RR interaction is unlikely to contribute to the elevated aldosterone levels in human (P)RR transgenic rats. This conclusion also implies that the aldosterone rise that often occurs during prolonged renin–angiotensin system blockade is rather due to the angiotensin II ‘escape’ during such blockade.

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Abstract 56: Candesartan And Valsartan, Contrary To Irbesartan, Are Potent Biased Antagonists Of Adrenal (beta)arrestin-dependent, Angiotensin II Type 1 Receptor-induced Aldosterone Production And Improve Cardiac Function Post-myocardial Infarction

Circulation Research ◽

10.1161/res.115.suppl_1.56 ◽

2014 ◽

Vol 115 (suppl_1) ◽

Author(s):

Anastasios Lymperopoulos ◽

Karlee Walklett ◽

Samalia Dabul ◽

Ashley Siryk ◽

Emmanuel Sturchler ◽

...

Keyword(s):

Myocardial Infarction ◽

Angiotensin Ii ◽

Cardiac Function ◽

G Protein ◽

Plasma Aldosterone ◽

Post Myocardial Infarction ◽

Aldosterone Production

Introduction: The scaffolding protein βarrestin1 (βarr1) by the angiotensin II (AngII) type 1 receptor (AT 1 R) mediates AngII-induced aldosterone production in vitro and physiologically in vivo, thereby exacerbating heart failure (HF) progression post-myocardial infarction (MI). Herein, we sought to investigate the relative potency of various AT 1 R antagonist drugs (sartans) at inhibiting βarr vs. G protein activation and hence aldosterone production in vitro and in vivo. We also investigated the alterations in plasma aldosterone levels conferred by these agents and their impact on cardiac function of post-MI rats. Methods: For the in vitro tests, transfected CHO and adrenocortical H295R cells were used. For in vivo studies, post-MI rats overexpressing βarr1 in their adrenals received 7-day-long treatments with the drugs of interest. Results: Among the sartans tested, candesartan and valsartan were the most potent βarr activation and βarr-mediated aldosterone production inhibitors in vitro, as well as the most “biased” antagonists towards βarr vs. G-protein inhibition. Conversely, losartan and irbesartan were the least potent βarr inhibitors and the least “biased” antagonists towards βarr inhibition. These in vitro findings were corroborated in vivo, since candesartan and valsartan, contrary to irbesartan, caused significant plasma aldosterone reductions in post-MI rats. Accordingly, cardiac ejection fraction (EF) and contractility were significantly augmented in candesartan- and valsartan-treated rats (EF: 41.1±1% and 40±1% respectively, vs. 35±0.3% for saline-treated), but further deteriorated in irbesartan-treated post-MI rats (EF: 32±1%, n=7 rats/group). Conclusions: These findings provide important insights that might aid pharmacotherapeutic decisions (i.e. individual agent selections) involving this commonly prescribed cardiovascular drug class (sartans).

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Polarized rabbit type 1 angiotensin II receptors manifest differential rates of endocytosis and recycling

AJP Cell Physiology ◽

10.1152/ajpcell.1995.269.4.c1048 ◽

1995 ◽

Vol 269 (4) ◽

pp. C1048-C1056 ◽

Cited By ~ 27

Author(s):

B. N. Becker ◽

H. F. Cheng ◽

K. D. Burns ◽

R. C. Harris

Keyword(s):

Angiotensin Ii ◽

Brush Border Membrane ◽

Cell Model ◽

Angiotensin Ii Receptors ◽

Ang Ii ◽

Pla2 Activity ◽

Compound I ◽

Pt Cell ◽

Permeable Supports

Receptor-mediated endocytosis and recycling have been described for extrarenal angiotensin II (ANG II) receptors. In proximal tubule (PT) epithelia expressing polarized ANG II receptors, these processes have not been examined as thoroughly. We utilized a PT cell model, LLC-PKCl4 cells stably transfected with rabbit type 1 ANG II receptor (AT1R) cDNA, to investigate these properties. LLC-PK-AT1R cells expressed the rabbit AT1R transcript and displayed losartan-inhibitable specific 125I-labeled ANG II binding at apical (AP) and basolateral (BL) membranes when grown on permeable supports. AP AT1R internalized 125I-ANG II more rapidly than BL AT1R, and phenylarsine oxide treatment inhibited AP AT1R internalization without significantly affecting BL AT1R endocytosis. Pertussis toxin had no effect on AP or BL AT1R endocytosis. In addition, AP AT1R recovered specific 125I-ANG II binding after ANG II treatment (a measure of recycling). BL AT1R displayed minimal recovery of 125I-ANG II binding after ANG II pretreatment. These data suggested that AP AT1R enter endocytic/endosomal pathways. Phospholipase A2 (PLA2) activity has been linked to endosomal fusion in other systems, and PT brush-border membrane AT1R also have been associated with PLA2 activity. LLC-PK-AT1R cells were therefore treated with quinacrine, a nonspecific PLA2 inhibitor, or Compound I (CI), a selective Ca(2+)-independent PLA2 inhibitor, to determine if PLA2 activity was linked to AT1R recycling. Both quinacrine and CI decreased AP AT1R recycling without affecting BL AT1R recycling. Polarized AT1R in LLC-PKCl4 cells thus display differential rates of endocytosis and recycling.(ABSTRACT TRUNCATED AT 250 WORDS)

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Aldosterone Breakthrough Caused by Chronic Blockage of Angiotensin II Type 1 Receptors in Human Adrenocortical Cells: Possible Involvement of Bone Morphogenetic Protein-6 Actions

Endocrinology ◽

10.1210/en.2007-1476 ◽

2008 ◽

Vol 149 (6) ◽

pp. 2816-2825 ◽

Cited By ~ 25

Author(s):

Hiroyuki Otani ◽

Fumio Otsuka ◽

Kenichi Inagaki ◽

Jiro Suzuki ◽

Tomoko Miyoshi ◽

...

Keyword(s):

Angiotensin Ii ◽

Bone Morphogenetic Protein ◽

Ang Ii ◽

Adrenocortical Cells ◽

Activin Receptor ◽

Morphogenetic Protein ◽

Receptor Like Kinase ◽

Aldosterone Production ◽

Aldosterone Breakthrough

Circulating aldosterone concentrations occasionally increase after initial suppression with angiotensin II (Ang II) converting enzyme inhibitors or Ang II type 1 receptor blockers (ARBs), a phenomenon referred to as aldosterone breakthrough. However, the underlying mechanism causing the aldosterone breakthrough remains unknown. Here we investigated whether aldosterone breakthrough occurs in human adrenocortical H295R cells in vitro. We recently reported that bone morphogenetic protein (BMP)-6, which is expressed in adrenocortical cells, enhances Ang II- but not potassium-induced aldosterone production in human adrenocortical cells. Accordingly, we examined the roles of BMP-6 in aldosterone breakthrough induced by long-term treatment with ARB. Ang II stimulated aldosterone production by adrenocortical cells. This Ang II stimulation was blocked by an ARB, candesartan. Interestingly, the candesartan effects on Ang II-induced aldosterone synthesis and CYP11B2 expression were attenuated in a course of candesartan treatment for 15 d. The impairment of candesartan effects on Ang II-induced aldosterone production was also observed in Ang II- or candesartan-pretreated cells. Levels of Ang II type 1 receptor mRNA were not changed by chronic candesartan treatment. However, BMP-6 enhancement of Ang II-induced ERK1/2 signaling was resistant to candesartan. The BMP-6-induced Smad1, -5, and -8 phosphorylation, and BRE-Luc activity was augmented in the presence of Ang II and candesartan in the chronic phase. Chronic Ang II exposure decreased cellular expression levels of BMP-6 and its receptors activin receptor-like kinase-2 and activin type II receptor mRNAs. Cotreatment with candesartan reversed the inhibitory effects of Ang II on the expression levels of these mRNAs. The breakthrough phenomenon was attenuated by neutralization of endogenous BMP-6 and activin receptor-like kinase-2. Collectively, these data suggest that changes in BMP-6 availability and response may be involved in the occurrence of cellular escape from aldosterone suppression under chronic treatment with ARB.

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SHEEP HYPOTHALAMUS CONTAINS A NON-ANGIOTENSIN LIGAND FOR TYPE 1 AND TYPE 2 ANGIOTENSIN II RECEPTORS

Clinical and Experimental Pharmacology and Physiology ◽

10.1111/j.1440-1681.1993.tb01741.x ◽

1993 ◽

Vol 20 (9) ◽

pp. 555-562 ◽

Cited By ~ 4

Author(s):

Julie Blasioli ◽

Athena Kladis ◽

Iain J. Clarke ◽

Duncan J. Campbell

Keyword(s):

Angiotensin Ii ◽

Angiotensin Ii Receptors

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Glucocorticoid and mineralocorticoid regulation of angiotensin II type 1 receptor binding and inositol triphosphate formation in WB cells

Journal of Endocrinology ◽

10.1677/joe.0.1620381 ◽

1999 ◽

Vol 162 (3) ◽

pp. 381-391 ◽

Cited By ~ 25

Author(s):

SG Shelat ◽

LM Flanagan-Cato ◽

SJ Fluharty

Keyword(s):

Angiotensin Ii ◽

Cell Line ◽

At1 Receptor ◽

Inositol Triphosphate ◽

Epithelial Cell Line ◽

Salt Appetite ◽

Pressor Responses ◽

The Brain

Mineralocorticoids, glucocorticoids, and angiotensin II (AngII) act cooperatively to maintain body fluid homeostasis. Mineralocorticoids, such as aldosterone and deoxycorticosterone-acetate (DOCA), function synergistically with AngII in the brain to increase salt appetite and blood pressure. In addition, glucocorticoids increase AngII-induced drinking and pressor responses and may also facilitate the actions of aldosterone on salt appetite. The AngII Type 1 (AT1) receptor mediates many of the physiological and behavioral actions of AngII. This receptor is coupled to the G-protein Gq, which mediates AngII-induced inositol triphosphate (IP3) formation. The WB cell line, a liver epithelial cell line that expresses the AT1 receptor, was used to examine the cellular basis of glucocorticoid and mineralocorticoid regulation of AT1 function. In this study corticosterone and dexamethasone treatments increased the number of AT1 receptors by activating the glucocorticoid receptor (GR). This increase in AT1 binding resulted in enhanced AngII-stimulated IP3 formation. However, only supraphysiological doses of aldosterone or DOCA increased AT1 binding, and this effect also was mediated by GR activation. Furthermore, despite evidence that mineralocorticoids and glucocorticoids function together to increase AngII-stimulated actions in vivo, aldosterone and dexamethasone did not act synergistically to affect AT1 binding, Gq expression, or IP3 formation. These results indicate that GR activation, and the subsequent increases in AT1 binding and in AngII-stimulated IP3 formation, may represent a cellular mechanism underlying the synergy between adrenal steroids and AngII.

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A functional comparison of the rat type-1 angiotensin II receptors (AT1AR and AT1BR)

Regulatory Peptides ◽

10.1016/0167-0115(95)00123-9 ◽

1995 ◽

Vol 60 (2-3) ◽

pp. 135-147 ◽

Cited By ~ 22

Author(s):

Mickey M. Martin ◽

C.Roger White ◽

Huaibin Li ◽

Patrick J. Miller ◽

Terry S. Elton

Keyword(s):

Angiotensin Ii ◽

Angiotensin Ii Receptors

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